Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain.
Molecular Biology Institute of Barcelona (IBMB-CSIC), 08028 Barcelona, Catalonia, Spain.
Mol Cell. 2014 Jan 9;53(1):115-26. doi: 10.1016/j.molcel.2013.11.015. Epub 2013 Dec 26.
Cells commit to a new cell cycle at Start by activation of the G1 Cdk-cyclin complex which, in turn, triggers a genome-wide transcriptional wave that executes the G1/S transition. In budding yeast, the Cdc28-Cln3 complex is regulated by an ER-retention mechanism that is important for proper cell size control. We have isolated small-cell-size CDC28 mutants showing impaired retention at the ER and premature accumulation of the Cln3 cyclin in the nucleus. The differential interactome of a quintuple Cdc28(wee) mutant pinpointed Whi7, a Whi5 paralog targeted by Cdc28 that associates to the ER in a phosphorylation-dependent manner. Our results demonstrate that the Cln3 cyclin and Whi7 act in a positive feedback loop to release the G1 Cdk-cyclin complex and trigger Start once a critical size has been reached, thus uncovering a key nonlinear mechanism at the earliest known events of cell-cycle entry.
细胞在启动时通过激活 G1 CDK-周期蛋白复合物来决定进入新的细胞周期，而后者又会引发全基因组转录波，从而执行 G1/S 转换。在芽殖酵母中，CDC28-Cln3 复合物受内质网保留机制的调节，该机制对于适当的细胞大小控制很重要。我们已经分离出了细胞尺寸变小的 CDC28 突变体，这些突变体在 ER 处的保留能力受损，Cln3 周期蛋白过早地在核内积累。五重 CDC28（wee）突变体的差异互作组鉴定出 Whi7，它是一个受 Cdc28 靶向的 Whi5 旁系同源物，以磷酸化依赖的方式与内质网结合。我们的结果表明，Cln3 周期蛋白和 Whi7 可以在正反馈回路中发挥作用，释放 G1 CDK-周期蛋白复合物，并在达到临界大小后触发起始，从而揭示了在已知的细胞周期进入的最早事件中一个关键的非线性机制。
